新型IDH1突变体选择性抑制剂的发现及抗白血病活性和机制研究

项目名称： 新型IDH1突变体选择性抑制剂的发现及抗白血病活性和机制研究

项目编号： No.81503110

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 高安慧

作者单位： 中国科学院上海药物研究所

项目金额： 17.9万元

中文摘要： “个性化药物”是当前抗肿瘤药物研发新趋势。异柠檬酸脱氢酶1（IDH1）在多种肿瘤中突变率高，成为潜在的抗肿瘤个性化药物靶点，其中IDH1突变的致癌性在白血病上得到证实。目前国际相关药物开发工作刚刚开始，如何快速有效的发现高选择性、高活性的IDH1突变体抑制剂是药物研发的关键问题。前期我们建立在白血病中高突变率的IDH1/R132H突变体筛选模型，通过高通量筛选获得5个与阳性化合物抑制活性相当且结构新颖的化合物，初步细胞水平的功能与机制研究显示其能够降低细胞内IDH1突变导致的2-HG累积，并促进白血病细胞的分化。本项目拟在此基础上，进一步开展化合物结构改造，依据对IDH1突变酶的高选择性、突变引起的代谢产物和表观遗传的变化，结合白血病细胞增殖和分化功能指标的策略，发现IDH1突变体高选择性高活性的结构新颖的候选化合物，为针对IDH1/R132突变体的抗肿瘤药物研发提供新的思路和候选化合物。

中文关键词： 分子靶向治疗；异柠檬酸脱氢酶1；基因突变；小分子抑制剂；白血病

英文摘要： Personalized medicine is a New Era of anti-cancer drugs development. One potential drug target is isocitrate dehydrogenase 1 (IDH1), a key metabolic enzyme of TCA cycle, which is mutated in multiple human cancers. Oncogenic properties of IDH1 mutation was presented through promoting leukemogenesis in vivo. But drug development targeted Mutant IDH1 is in the initial stage now. A key challenge is the development of drug strategies for selective and active inhibitor in terms of IDH1 mutant signatures. Preliminary work, based on IDH1/R132H which is the vast majority of IDH1 mutations in leukemia, we have established a high-throughput screening assay that utilized the ability of the IDH1/R132H mutant to produce R-2-hydroxyglutarate (2-HG). After random screening, five selective IDH1/R132H inhibitors identified through a high-throughput screen reduced 2-HG and promoted differentiation of leukemia cell. In this study, we will optimize the drug-like properties of known 5 inhibitors. Toward the aim of developing IDH1 mutant inhibitors, we will use approaches according to selectivity of IDH1 mutant, cellular metabolite, epigenetic effects, and the growth and differentiation of leukemia cells to identify the hit compounds quickly. And we hope these effects can not only provide new candidate for mutant IDH1-dependent cancer, but also benefit other researchers for further mutant IDH1 inhibitor development.

英文关键词： Molecular targeting therapy;Isocitrate dehydrogenase 1;Mutation ;Inhibitor;Leukemia